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1.  Extravascular lung water and pulmonary arterial wedge pressure for fluid management in patients with acute respiratory distress syndrome 
Extravascular lung water (EVLW) is a sensitive prognostic indicator of pulmonary edema. Thus, EVLW may be an advantageous method of fluid management. This study aims to evaluate the outcomes of using EVLW and pulmonary artery wedge pressure (PAWP) as strategies for fluid management in patients with acute respiratory distress syndrome (ARDS).
Twenty-nine patients were randomly divided into the EVLW and PAWP groups. The survival rate, ICU (Intensive Care Unit) length of stay, duration of mechanical ventilation, acute lung injury scores, and oxygenation index of the EVLW and PAWP groups were compared.
No significant difference in the survival rates at 28 and 60 days (d) after treatment was found between the two groups (p = 0.542). The duration of mechanical ventilation and ICU length of stay were significantly lower (p < 0.05) in the EVLW group than in the PAWP group. The 7 d cumulative fluid balance was -783 ± 391 ml in the EVLW group and -256 ± 514 ml in the PAWP group (p < 0.05). Compared with the PAWP group, the EVLW group showed improved oxygenation index (p = 0.006).
EVLW for fluid management improved clinical results in patients with ARDS better than PAWP.
PMCID: PMC3906773  PMID: 24428957
Acute respiratory distress syndrome; Extravascular lung water; Fluid management; Pulmonary artery wedge pressure
2.  Alterations in serum immunoglobulin levels in workers occupationally exposed to trichloroethylene 
Carcinogenesis  2012;34(4):799-802.
Trichloroethylene (TCE) has been associated with a variety of immunotoxic effects and may be associated with an increased risk of non-Hodgkin lymphoma (NHL). Altered serum immunoglobulin (Ig) levels have been reported in NHL patients and in animals exposed to TCE. Recently, we reported that occupational exposure to TCE is associated with immunosuppressive effects and immune dysfunction, including suppression of B-cell counts and activation, even at relatively low levels. We hypothesized that TCE exposure would also affect Ig levels in humans. We measured serum levels of IgG, IgM and IgE, by enzyme-linked immunosorbent assay, in TCE-exposed workers (n = 80) and unexposed controls (n = 45), matched by age and gender, in a cross-sectional, molecular epidemiology study of occupational exposure to TCE in Guangdong, China. Exposed workers had about a 17.5% decline in serum levels of IgG compared with unexposed controls (P = 0.0002). Similarly, serum levels of IgM were reduced by about 38% in workers exposed to TCE compared with unexposed controls (P < 0.0001). Serum levels of both IgG and IgM were significantly decreased in workers exposed to TCE levels below 12 p.p.m., the median exposure level. Adjustment for B-cell counts had minimal impact on our findings. IgE levels were not significantly different between exposed and control subjects. These results provide further evidence that TCE is immunotoxic at relatively low exposure levels and provide additional biologic plausibility for the reported association of TCE with NHL.
PMCID: PMC3616671  PMID: 23276795
3.  Mov10 and APOBEC3G Localization to Processing Bodies Is Not Required for Virion Incorporation and Antiviral Activity 
Journal of Virology  2013;87(20):11047-11062.
Mov10 and APOBEC3G (A3G) localize to cytoplasmic granules called processing bodies (P bodies), incorporate into human immunodeficiency virus type 1 (HIV-1) virions, and inhibit viral replication. The functional relevance of Mov10/A3G P-body localization to virion incorporation and antiviral activity has not been fully explored. We found that a helicase V mutant of Mov10 exhibits significantly reduced localization to P bodies but still efficiently inhibits viral infectivity via virion incorporation. Disruption of the P bodies by DDX6 knockdown also confirmed Mov10 antiviral activity without P-body localization. In addition, overexpression of SRP19, which binds to 7SL RNA, depleted A3G from P bodies but did not affect its virion incorporation. Sucrose gradient sedimentation assays revealed that the majority of Mov10, A3G, HIV-1 RNA, and Gag formed high-molecular-mass (HMM) complexes that are converted to low-molecular-mass (LMM) complexes after RNase A treatment. In contrast, the P-body markers DCP2, LSM1, eIF4e, DDX6, and AGO1 were in LMM complexes, whereas AGO2, an effector protein of the RNA-induced silencing complex that localizes to P bodies, was present in both LMM and HMM complexes. Depletion of AGO2 indicated that RNA-induced silencing function is required for Mov10's ability to reduce Gag expression upon overexpression, but not its virion incorporation or effect on virus infectivity. We conclude that the majority of Mov10 and A3G are in HMM complexes, whereas most of the P-body markers are in LMM complexes, and that virion incorporation and the antiviral activities of Mov10 and A3G do not require their localization to P bodies.
PMCID: PMC3807276  PMID: 23926332
4.  Comprehensive epigenetic analysis of Notch pathway in high-grade serous ovarian cancer 
Gynecologic oncology  2012;128(3):506-511.
Gene methylation and other epigenetic modifications of gene regulation have been implicated in the growth of ovarian cancer, but the clinical significance of such modifications in the Notch pathway in high-grade serous ovarian cancer (HGS-OvCa) is not well understood. We used The Cancer Genome Atlas (TCGA) data to study the clinical relevance of epigenetic modifications of Notch pathway genes.
We analyzed the interaction of DNA methylation and miRNAs with gene expression data for Notch family members with the Spearman rank correlation test and explored potential relationships with overall survival (OS) with the log-rank test. We downloaded clinical data, level 3 gene expression data, and level 3 DNA methylation data for 480 patients with stage II-IV HGS-OvCa from TCGA data portal. Patients were randomly divided into training and validation cohorts for survival analyses. In each set, patients were grouped into percentiles according to methylation and microRNA (miRNA) or messenger RNA (mRNA) levels. We used several algorithms to predict miRNA-mRNA interaction.
There were significant inverse relationships between methylation status and mRNA expression for PPARG, CCND1, and RUNX1. For each of these genes, patients with a lower methylation level and higher expression level had significantly poorer OS than did patients with a higher methylation level and lower expression level. We also found a significant inverse relationship between miRNAs and mRNA expression for CCND1, PPARG, and RUNX1. By further analyzing the effect of miRNAs on gene expression and OS, we found that patients with higher levels of CCND1, PPARG, and RUNX1 expression and lower expression levels of their respective miRNAs (502-5p, 128, and 215/625) had significantly poorer OS.
Epigenetic alterations of multiple Notch target genes and pathway interacting genes (PPARG, CCND1, and RUNX1) may relate to activation of this pathway and poor survival of patients with HGS-OvCa.
PMCID: PMC3645276  PMID: 23200915
Notch pathway; high-grade serous ovarian carcinoma; epigenetic alterations; High-grade serous ovarian cancer; The Cancer Genome Atlas; Epigenetic modifications of gene regulation
5.  Diversity of epothilone producers among Sorangium strains in producer-positive soil habitats 
Microbial Biotechnology  2013;7(2):130-141.
Large-scale surveys show that the anti-tumour compounds known as epothilones are produced by only a small proportion of Sorangium strains, thereby greatly hampering the research and development of these valuable compounds. In this study, to investigate the niche diversity of epothilone-producing Sorangium strains, we re-surveyed four soil samples where epothilone producers were previously found. Compared with the < 2.5% positive strains collected from different places, epothilone producers comprised 25.0–75.0% of the Sorangium isolates in these four positive soil samples. These sympatric epothilone producers differed not only in their 16S rRNA gene sequences and morphologies but also in their production of epothilones and biosynthesis genes. A further exploration of 14 soil samples collected from a larger area around a positive site showed a similar high positive ratio of epothilone producers among the Sorangium isolates. The present results suggest that, in an area containing epothilone producers, the long-term genetic variations and refinements resulting from selective pressure form a large reservoir of epothilone-producing Sorangium strains with diverse genetic compositions.
PMCID: PMC3937717  PMID: 24308800
6.  Promotion of minTBP-1-PRGDN on the attachment, proliferation and collagen I synthesis of human keratocyte on titanium 
To investigate the influence of minTBP-1-PRGDN on the attachment, proliferation and collagen I synthesis of human keratocyte on titanium (Ti) surface.
The chimeric peptide RKLPDAPRGDN (minTBP-1-PRGDN) was synthesized by connecting RKLPDA (minTBP-1) to the N-terminal of PRGDN, the influence of minTBP-1-PRGDN on the attachment, proliferation and collagen I synthesis of human keratocyte on Ti surface were tested using PRGDN and minTBP-1as controls. The keratocytes attached to the surface of Ti were either stained with FITC-labeled phalloidin and viewed with fluorescence microscope or quantified with alamar Blue method. The proliferation of keratocytes on Ti were quantified with 3-(4,5-dim- ethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide up-taking methods. The secretion of type I collagen were determined using an ELISA kit.
The results showed that minTBP-1-PRGDN at a concentration of 100ng/mL was the most potent peptide to enhance the attachment of human keratocytes to the surface of Ti (1.40±0.03 folds, P=0.003), to promote the proliferation (1.26±0.05 folds, P=0.014) and the synthesis of type I collagen (1.530±0.128, P=0.008). MinTBP-1 at the same concentration could only promote the attachment (1.13±0.04 folds, P=0.020) and proliferation(1.15±0.06 folds, P=0.021), while PRGDN had no significant influence (P>0.05).
Our data shows that the novel chimeric peptide minTBP-1-PRGDN could promote the attachment, proliferation and type I collagen synthesis of human keratocytes on the surface of Ti.
PMCID: PMC3949453  PMID: 24634858
minTBP-1-PRGDN; titanium; cell attachment; proliferation; type I collagen
7.  Schistosoma japonicum Egg Specific Protein SjE16.7 Recruits Neutrophils and Induces Inflammatory Hepatic Granuloma Initiation 
Neutrophils are known to play a major role in the egg granulomatous lesions caused by Schistosoma japonicum, but the precise mechanism by which eggs recruit or active neutrophil is unknown. Here we report S. japonicum egg specific EF-hand protein-SjE16.7 is a potent neutrophil recruiter and initiates the egg associated inflammatory granuloma in schistosomiasis. We show that the expression of SjE16.7 at level of both mRNA and protein is restricted to the egg stage. It locates in the miracidium and subshell area of the egg and can be secreted by the egg. The antigenic properties of SjE16.7 strongly suggest a role for SjE16.7 as an egg-derived molecule involved in host-parasite interactions. To study SjE16.7 functions in vivo, we challenged murine air pouch with recombinant SjE16.7. The results showed SjE16.7 trigged more inflammatory cell infiltration than vehicle or control protein. Using peritoneal exudate neutrophils from mice, we found that SjE16.7 significantly induced neutrophil chemotaxis in vitro, and the observed phenotypes were associated with enhanced Rac GTPase activation in SjE16.7 treated cells. Finally, in vivo hepatic granuloma formation model showed SjE16.7 coupled beads recruited more inflammatory cell infiltration than control beads. Our findings suggest SjE16.7 is an important pathogenic factor derived from egg. By recruiting neutrophils and inducing local inflammation, SjE16.7 facilitates eggs to be excreted through gut tissues and also initiates pathology in the liver; therefore SjE16.7 is a possible target for the prevention and treatment of schistosomiasis.
Author Summary
As a neglected disease, schistosomiasis continues to be a significant cause of parasitic morbidity and mortality worldwide. Schistosoma japonicum is one of the major causative agents of human schistosomiasis. Trapped in the liver or intestinal tissue, S. japonicum eggs are the main cause of pathology following infection. They induce vigorous immune responses from the host, which facilitate the passage of the eggs from the tissue to the gut lumen and cause the pathology in liver. In this paper, we described, for the first time, S. japonicum egg specific EF-hand protein-SjE16.7 is a potent neutrophil recruiter and initiates the egg associated inflammatory granuloma in schistosomiasis. This study presents a precise mechanism by which eggs recruit neutrophil and induce inflammatory response. It furthers our understanding of the immunopathogenesis of human schistosomiasis. In addition, it provides a potential target for the prevention and treatment of this globally important parasite.
PMCID: PMC3923719  PMID: 24551263
8.  Deep brain stimulation for dystonia 
Deep brain stimulation (DBS) is an effective surgical treatment for medication-refractory movement disorders, and has been approved by the United States Food and Drug Administration for treatment of dystonia. The success of DBS in the treatment of dystonia depends on our understanding of the anatomy and physiology of this disorder and close collaboration between neurosurgeons, neurologists, clinical neurophysiologists, neuroradiologists and neuropsychologists. Currently, pallidal DBS is an established treatment option for medically refractive dystonia. This review is intended to provide a comprehensive review of the use of DBS for dystonia, focusing mainly on the surgical aspects, clinical outcome, MRI findings and side effects of DBS.
PMCID: PMC3902434  PMID: 24444300
Dystonia; Deep brain stimulation; Surgical outcomes; Neuromodulation; Globus pallidus
9.  Active Immunity Induced by Passive IgG Post-Exposure Protection against Ricin 
Toxins  2014;6(1):380-393.
Therapeutic antibodies can confer an instant protection against biothreat agents when administered. In this study, intact IgG and F(ab’)2 from goat anti-ricin hyperimmune sera were compared for the protection against lethal ricin mediated intoxication. Similar ricin-binding affinities and neutralizing activities in vitro were observed between IgG and F(ab’)2 when compared at the same molar concentration. In a murine ricin intoxication model, both IgG and F(ab’)2 could rescue 100% of the mice by one dose (3 nmol) administration of antibodies 1 hour after 5 × LD50 ricin challenge. Nine days later, when the rescued mice received a second ricin challenge (5 × LD50), only the IgG-treated mice survived; the F(ab’)2-treated mice did not. The experimental design excluded the possibility of residual goat IgG responsible for the protection against the second ricin challenge. Results confirmed that the active immunity against ricin in mice was induced quickly following the passive delivery of a single dose of goat IgG post-exposure. Furthermore, it was demonstrated that the induced active immunity against ricin in mice lasted at least 5 months. Therefore, passive IgG therapy not only provides immediate protection to the victim after ricin exposure, but also elicits an active immunity against ricin that subsequently results in long term protection.
PMCID: PMC3920268  PMID: 24451844
passive antibody therapy; ricin intoxication; post-exposure; IgG; F(ab’)2; active immunity
10.  Icaritin Inhibits JAK/STAT3 Signaling and Growth of Renal Cell Carcinoma 
PLoS ONE  2013;8(12):e81657.
Signal transducer and activator of transcription-3 (STAT3) is critical for cancer progression by regulating tumor cell survival, proliferation, and angiogenesis. Herein, we investigated the regulation of STAT3 activation and the therapeutic effects of Icaritin, a prenyl flavonoid derivative from Epimedium Genus, in renal cell carcinoma (RCC). Icaritin showed significant anti-tumor activity in the human and mouse RCC cell lines, 786-O and Renca, respectively. Icaritin inhibited both constitutive and IL-6-induced phospho-STAT3 (STAT3Y705) and reduced the level of STAT3-regulated proteins Bcl-xL, Mcl-1, Survivin, and CyclinD1 in a dose-dependent manner. Icaritin also inhibited activation of Janus-activated kinase-2 (JAK2), while it showed minimal effects on the activation of other key signaling pathways, including AKT and MAPK. Expression of the constitutively active form of STAT3 blocked Icaritin-induced apoptosis, while siRNA directed against STAT3 potentiated apoptosis. Finally, Icaritin significantly blunted RCC tumor growth in vivo, reduced STAT3 activation, and inhibited Bcl-xL and Cyclin E, as well as VEGF expression in tumors, which was associated with reduced tumor angiogenesis. Overall, these results suggest that Icaritin strongly inhibits STAT3 activation and is a potentially effective therapeutic option for the treatment of renal cell carcinoma.
PMCID: PMC3855768  PMID: 24324713
11.  A Phase II Evaluation of Aflibercept in the Treatment of Recurrent or Persistent Endometrial Cancer: a Gynecologic Oncology Group study 
Gynecologic oncology  2012;127(3):538-543.
Aflibercept targets vascular endothelial growth factor and placental growth factor. We evaluated activity and toxicity of aflibercept in recurrent/persistent endometrial cancer patients. Biomarkers and association with clinical characteristics and outcome were explored.
Eligible patients had measurable disease; 1–2 prior cytotoxic regimens; performance status 0–2. Aflibercept 4 mg/kg IV q14 days (28-day cycles) was administered until disease progression or prohibitive toxicity. Primary endpoints were the proportion of patients with progression-free survival at six months (PFS6) and tumor response rate. A flexible two-stage group sequential design to detect 20% increases in the proportion of patients responding or enduring PFS6 with 90% power (α=10%) was employed.
Forty-nine patients were enrolled; five were excluded: wrong primary (2), second primary (1), wrong cell type (1); never treated (1). Median age was 64 (range 48–83). Eighteen patients (41%) had two prior regimens; 61%(27) had prior radiation. The PFS6 rate was 41%; three patients 7%, 90% CI:2–17) had partial response. Of note, 10 patients (23%) met the PFS6 endpoint without starting a subsequent therapy; the remaining eight patients discontinued therapy for toxicity and started another therapy before six months elapsed. Median PFS and overall survival were 2.9 months and 14.6 months, respectively. Significant grade 3/4 toxicities were: cardiovascular (23%/5%), constitutional (7%/0), hemorrhage (2%/5%), metabolic (7%/2%), pain (18%/0). Two treatment-related deaths were recorded: GI perforation (1), arterial rupture (1). FGF1 expression was associated with response.
Aflibercept met pretrial activity parameters, but was associated with significant toxicity at this dose and schedule in this population.
PMCID: PMC3568489  PMID: 22922531
Aflibercept; endometrial cancer; VEGF Trap; Toxicity; Fibroblast growth factor
12.  Alteration of Dynein Function Affects α-Synuclein Degradation via the Autophagosome-Lysosome Pathway 
Growing evidence suggests that dynein dysfunction may be implicated in the pathogenesis of neurodegeneration. It plays a central role in aggresome formation, the delivery of autophagosome to lysosome for fusion and degradation, which is a pro-survival mechanism essential for the bulk degradation of misfolded proteins and damaged organells. Previous studies reported that dynein dysfuntion was associated with aberrant aggregation of α-synuclein, which is a major component of inclusion bodies in Parkinson’s disease (PD). However, it remains unclear what roles dynein plays in α-synuclein degradation. Our study demonstrated a decrease of dynein expression in neurotoxin-induced PD models in vitro and in vivo, accompanied by an increase of α-synuclein protein level. Dynein down-regulation induced by siRNA resulted in a prolonged half-life of α-synuclein and its over-accumulation in A53T overexpressing PC12 cells. Dynein knockdown also prompted the increase of microtubule-associated protein 1 light chain 3 (LC3-II) and sequestosome 1 (SQSTM1, p62) expression, and the accumulation of autophagic vacuoles. Moreover, dynein suppression impaired the autophagosome fusion with lysosome. In summary, our findings indicate that dynein is critical for the clearance of aberrant α-synuclein via autophagosome-lysosome pathway.
PMCID: PMC3876108  PMID: 24351814
dynein; α-synuclein; Parkinson’s disease; autophagy; autolysosome
13.  The Influence of Long Term Hydrochlorothiazide Administration on the Relationship between Renin-Angiotensin-Aldosterone System Activity and Plasma Glucose in Patients with Hypertension 
Objective. To observe the relationship between changes in renin-angiotensin-aldosterone system (RAAS) activity and blood plasma glucose after administration of hydrochlorothiazide (HCTZ) for one year in patients with hypertension. Methods. 108 hypertensive patients were given 12.5 mg HCTZ per day for one year. RAAS activity, plasma glucose levels, and other biochemical parameters, as well as plasma oxidized low density lipoprotein (oxLDL) levels, were measured and analyzed at baseline, six weeks, and one year after treatment. Results. After one year of treatment, the reduction in plasma glucose observed between the elevated plasma renin activity (PRA) group (−0.26 ± 0.26 mmol/L) and the nonelevated PRA group (−1.36 ± 0.23 mmol/L) was statistically significant (P < 0.05). The decrease of plasma glucose in the elevated Ang II group (−0.17 ± 0.18 mmol/L) compared to the nonelevated Ang II group (−1.07 ± 0.21 mmol/L) was statistically significant (P < 0.05). The proportion of patients with elevated plasma glucose in the elevated Ang II group (40.5%) was significantly higher than those in the nonelevated Ang II group (16.3%) (P < 0.05). The relative oxLDL level was not affected by the treatment. Conclusions. Changes in RAAS activity were correlated with changes in plasma glucose levels after one year of HCTZ therapy.
PMCID: PMC3852583  PMID: 24349612
14.  Role of Intracellular Stochasticity in Biofilm Growth. Insights from Population Balance Modeling 
PLoS ONE  2013;8(11):e79196.
There is increasing recognition that stochasticity involved in gene regulatory processes may help cells enhance the signal or synchronize expression for a group of genes. Thus the validity of the traditional deterministic approach to modeling the foregoing processes cannot be without exception. In this study, we identify a frequently encountered situation, i.e., the biofilm, which has in the past been persistently investigated with intracellular deterministic models in the literature. We show in this paper circumstances in which use of the intracellular deterministic model appears distinctly inappropriate. In Enterococcus faecalis, the horizontal gene transfer of plasmid spreads drug resistance. The induction of conjugation in planktonic and biofilm circumstances is examined here with stochastic as well as deterministic models. The stochastic model is formulated with the Chemical Master Equation (CME) for planktonic cells and Reaction-Diffusion Master Equation (RDME) for biofilm. The results show that although the deterministic model works well for the perfectly-mixed planktonic circumstance, it fails to predict the averaged behavior in the biofilm, a behavior that has come to be known as stochastic focusing. A notable finding from this work is that the interception of antagonistic feedback loops to signaling, accentuates stochastic focusing. Moreover, interestingly, increasing particle number of a control variable could lead to an even larger deviation. Intracellular stochasticity plays an important role in biofilm and we surmise by implications from the model, that cell populations may use it to minimize the influence from environmental fluctuation.
PMCID: PMC3827321  PMID: 24232571
15.  Phenotypic characterization of the foldase homologue PrsA in Streptococcus mutans 
Molecular oral microbiology  2012;28(2):10.1111/omi.12014.
Streptococcus mutans is generally considered to be the principal etiological agent for dental caries. Many of the proteins necessary for its colonization of the oral cavity and pathogenesis are exported to the cell surface or the extracellular matrix, a process that requires the assistance of the export machineries. Bioinformatic analysis revealed that the S. mutans genome contains a prsA gene, whose counterparts in other gram positive bacteria, including Bacillus and Lactococcus encode functions involved in protein post-export. In this study, we constructed a PrsA-deficient derivative of S. mutans and demonstrated that the prsA mutant displayed an altered cell wall/ membrane protein profile as well as cell surface related phenotypes, including auto-aggregation, increased surface hydrophobicity, and abnormal biofilm formation. Further analysis revealed that the disruption of the prsA gene resulted in reduced insoluble glucan production by cell surface localized glucosyltransferases, and mutacin as well as cell surface-display of a heterologous expressed GFP fusion to the cell surface protein SpaP. Our study suggested that PrsA in S. mutans encodes functions similar to the ones identified in Bacillus, and thus is likely involved in protein post-export.
PMCID: PMC3819222  PMID: 23241367
foldase protein PrsA; protein secretion; Streptococcus mutans
16.  Effects of Exopolysaccharide Production on Liquid Vegetative Growth, Stress Survival and Stationary Phase Recovery in Myxococcus xanthus 
Journal of microbiology (Seoul, Korea)  2012;50(2):10.1007/s12275-012-1349-5.
Exopolysaccharide (EPS) of Myxococcus xanthus is a well-regulated cell surface component. In addition to its known functions for social motility and fruiting body formation on solid surfaces, EPS has also been proposed to play a role in multi-cellular clumping in liquid medium, though this phenomenon has not been well studied. In this report, we confirmed that M. xanthus clumps formed in liquid were correlated with EPS levels and demonstrated that the EPS encased cell clumps exhibited biofilm-like structures. The clumps protected the cells at physiologically relevant EPS concentrations, while cells lacking EPS exhibited significant reduction in long-term viability and resistance to stressful conditions. However, excess EPS production was counterproductive to vegetative growth and viable cell recovery declined in extended late stationary phase as cells became trapped in the matrix of clumps. Therefore, optimal EPS production by M. xanthus is important for normal physiological functions in liquid.
PMCID: PMC3819231  PMID: 22538652
Myxococcus xanthus; exopolysaccharide; vegetative growth; stress survival; stationary phase recovery
17.  C-Reactive Protein for Predicting Prognosis and Its Gender-Specific Associations with Diabetes Mellitus and Hypertension in the Development of Coronary Artery Spasm 
PLoS ONE  2013;8(10):e77655.
While hypertension is negatively associated with coronary artery spasm (CAS), scarce data are available on diabetes mellitus in relation to CAS. In addition, outcome prediction in patients with CAS is challenging due to the lack of appropriate biomarkers. Therefore, we sought to identify the roles that gender, high-sensitivity C-reactive protein (hs-CRP), diabetes mellitus and hypertension play in CAS development and prognosis.
Methodology/Prinicpal Findings
Patients (350 women and 547 men) undergoing diagnostic coronary angiography with or without proven CAS but without obstructive stenosis were evaluated at long-term follow-up (median 102 months). Diabetic women and diabetic men with low hs-CRP levels had a low and high risk of CAS (odds ratio [OR]: 0.16, 95% confidence interval [CI]: 0.01–1.88 and OR: 5.02, 95% CI: 1.03–24.54, respectively). The ORs of CAS in both women and men with the highest hs-CRP tertile (>3 mg/L) reduced from 4.41 to 1.45 and 2.98 to 1.52, respectively, if they had diabetes mellitus, and from 9.68 to 2.43 and 2.60 to 1.75, respectively, if they had hypertension. Hypertension had a more negative effect on CAS development in diabetic than non-diabetic women, which was not observed in men. The highest hs-CRP tertile was an independent predictor of adverse outcomes. Patients with the highest hs-CRP tertile had more coronary events than patients with the lowest hs-CRP tertitle (p = 0.021, log-rank test).
Diabetes mellitus contributes to CAS development in men with low hs-CRP levels, but not in women. There are negative effects of diabetes mellitus and hypertension on CAS development in patients with high hs-CRP levels and especially in women. Elevated hs-CRP level independently predicts adverse outcomes.
PMCID: PMC3810263  PMID: 24204905
18.  The Interactive Effects of Transgenically Overexpressed 1Ax1 with Various HMW-GS Combinations on Dough Quality by Introgression of Exogenous Subunits into an Elite Chinese Wheat Variety 
PLoS ONE  2013;8(10):e78451.
Seed storage proteins in wheat endosperm, particularly high-molecular-weight glutenin subunits (HMW-GS), are primary determinants of dough properties, and affect both end-use quality and grain utilization of wheat (Triticum aestivum L). In order to investigate the interactive effects between the transgenically overexpressed 1Ax1 subunit with different HMW-GS on dough quality traits, we developed a set of 8 introgression lines (ILs) overexpressing the transgenic HMW-glutenin subunit 1Ax1 by introgression of this transgene from transgenic line B102-1-2/1 into an elite Chinese wheat variety Chuanmai107 (C107), using conventional crossing and backcrossing breeding technique. The donor C107 strain lacks 1Ax1 but contains the HMW-GS pairs 1Dx2+1Dy12 and 1Bx7+1By9. The resultant ILs showed robust and stable expression of 1Ax1 even after five generations of self-pollination, and crossing/backcrossing three times. In addition, overexpression of 1Ax1 was compensated by the endogenous gluten proteins. All ILs exhibited superior agronomic performance when compared to the transgenic parent line, B102-1-2/1. Mixograph results demonstrated that overexpressed 1Ax1 significantly improved dough strength, resistance to extension and over-mixing tolerance, in the targeted wheat cultivar C107. Further, comparisons among the ILs showed the interactive effects of endogenous subunits on dough properties when 1Ax1 was overexpressed: subunit pair 17+18 contributed to increased over-mixing tolerance of the dough; expression of the Glu-D1 allele maintained an appropriate balance between x-type and y-type subunits and thereby improved dough quality. It is consistent with ILs C4 (HMW-GS are 1, 17+18, 2+12) had the highest gluten index and Zeleny sedimentation value. This study demonstrates that wheat quality could be improved by using transgenic wheat overexpressing HMW-GS and the feasibility of using such transgenic lines in wheat quality breeding programs.
PMCID: PMC3805546  PMID: 24167625
19.  Inheritable and Precise Large Genomic Deletions of Non-Coding RNA Genes in Zebrafish Using TALENs 
PLoS ONE  2013;8(10):e76387.
Transcription activator-like effector nucleases (TALENs) have so far been applied to disrupt protein-coding genes which constitute only 2–3% of the genome in animals. The majority (70–90%) of the animal genome is actually transcribed as non-coding RNAs (ncRNAs), yet the lack of efficient tools to knockout ncRNA genes hinders studies on their in vivo functions. Here we have developed novel strategies using TALENs to achieve precise and inheritable large genomic deletions and knockout of ncRNA genes in zebrafish. We have demonstrated that individual miRNA genes could be disrupted using one pair of TALENs, whereas large microRNA (miRNA) gene clusters and long non-coding RNA (lncRNA) genes could be precisely deleted using two pairs of TALENs. We have generated large genomic deletions of two miRNA clusters (the 1.2 kb miR-17-92 cluster and the 79.8 kb miR-430 cluster) and one long non-coding RNA (lncRNA) gene (the 9.0 kb malat1), and the deletions are transmitted through the germline. Taken together, our results establish TALENs as a robust tool to engineer large genomic deletions and knockout of ncRNA genes, thus opening up new avenues in the application of TALENs to study the genome in vivo.
PMCID: PMC3794983  PMID: 24130773
20.  Co-infections with Babesia microti and Plasmodium parasites along the China-Myanmar border 
Babesiosis is an emerging health risk in several parts of the world. However, little is known about the prevalence of Babesia in malaria-endemic countries. The area along the China-Myanmar border in Yunnan is a main endemic area of malaria in P.R. China, however, human infection with Babesia microti (B. microti) is not recognized in this region, and its profile of co-infection is not yet clear.
To understand its profile of co-infections with B. microti, our investigation was undertaken in the malaria-endemic area along the China-Myanmar border in Yunnan between April 2012 and June 2013. Four parasite species, including B. microti, Plasmodium falciparum (P. falciparum), P. vivax, and P. malariae, were identified among 449 suspected febrile persons detected by nested polymerase chain reaction (PCR) assay based on small subunit ribosomal ribonucleic acid (RNA) genes of B. microti and Plasmodium spp.
Of all the collected samples from febrile patients, mono-infection with B. microti, P. vivax, P. falciparum, and P. malariae accounted for 1.8% (8/449), 9.8% (44/449), 2.9% (13/449), and 0.2% (1/449), respectively. The rate of mixed infections of B. microti with P. falciparum or P. vivax are both 0.2% (1/449), and mixed infections of P. falciparum and P. vivax accounted for 1.1% (5/449).
This report supports the hypothesis that babesiosis caused by B. microti is emerging along the China-Myanmar border in the Yunnan province, P.R. China, but it was ignored because of low parasitemia or mixed infection with Plasmodium spp. More sensitive and specific diagnosis methods are needed to find the rapid response mechanism of emergency for babesiosis and malaria co-prevalence areas.
PMCID: PMC3819642  PMID: 24090043
Babesia; Plasmodium; Co-infection; China-Myanmar border
21.  Previous Lung Diseases and Lung Cancer Risk: A Pooled Analysis From the International Lung Cancer Consortium 
American Journal of Epidemiology  2012;176(7):573-585.
To clarify the role of previous lung diseases (chronic bronchitis, emphysema, pneumonia, and tuberculosis) in the development of lung cancer, the authors conducted a pooled analysis of studies in the International Lung Cancer Consortium. Seventeen studies including 24,607 cases and 81,829 controls (noncases), mainly conducted in Europe and North America, were included (1984–2011). Using self-reported data on previous diagnoses of lung diseases, the authors derived study-specific effect estimates by means of logistic regression models or Cox proportional hazards models adjusted for age, sex, and cumulative tobacco smoking. Estimates were pooled using random-effects models. Analyses stratified by smoking status and histology were also conducted. A history of emphysema conferred a 2.44-fold increased risk of lung cancer (95% confidence interval (CI): 1.64, 3.62 (16 studies)). A history of chronic bronchitis conferred a relative risk of 1.47 (95% CI: 1.29, 1.68 (13 studies)). Tuberculosis (relative risk = 1.48, 95% CI: 1.17, 1.87 (16 studies)) and pneumonia (relative risk = 1.57, 95% CI: 1.22, 2.01 (12 studies)) were also associated with lung cancer risk. Among never smokers, elevated risks were observed for emphysema, pneumonia, and tuberculosis. These results suggest that previous lung diseases influence lung cancer risk independently of tobacco use and that these diseases are important for assessing individual risk.
PMCID: PMC3530374  PMID: 22986146
bronchitis; chronic; emphysema; lung diseases; lung neoplasms; meta-analysis; pneumonia; pulmonary disease; chronic obstructive; tuberculosis
22.  Phase II evaluation of Dasatinib in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: A Gynecologic Oncology Group study 
Gynecologic oncology  2012;127(1):70-74.
Preclinical data suggest an important role for the sarcoma proto-oncogene tyrosine kinase (SRC) in the oncogenesis of epithelial ovarian cancer (EOC) or primary peritoneal carcinoma (PPC). The Gynecologic Oncology Group (GOG) conducted a Phase II trial to evaluate the efficacy and safety of dasatinib, an oral SRC-family inhibitor in EOC/PPC and explored biomarkers for possible association with clinical outcome.
Eligible women had measurable, recurrent or persistent EOC/PPC and had received one or two prior regimens which must have contained a platinum and a taxane. Patients were treated with 100 mg orally daily of dasatinib continuously until progression of disease or adverse effects prevented further treatment. Primary endpoints were progression-free survival (PFS) ≥6 months and response rate. Serial plasma samples were assayed for multiple biomarkers. Circulating free DNA was quantified as were circulating tumor and endothelial cells.
Thirty-five (35) patients were enrolled in a two-stage sequential design. Of the 34 eligible and evaluable patients, 20.6% (90% confidence interval: 10.1%, 35.2%) had a PFS ≥6 months; there were no objective responses. Grade 3–4 toxicities were gastrointestinal (mostly nausea and emesis; n=4), pulmonary (dyspnea and/or pleural effusion; n=4) and pain (n=5), and infrequent instances of anemia, malaise, insomnia, rash, and central nervous system hemorrhage. Lack of clinical activity limited any correlation of biomarkers with outcome.
Dasatinib has minimal activity as a single-agent in patients with recurrent EOC/PPC.
PMCID: PMC3748717  PMID: 22710075
dasatinib; ovarian; cancer; SRC; inhibition
23.  A Study on the Mechanism of Cinobufagin in the Treatment of Paw Cancer Pain by Modulating Local β-Endorphin Expression In Vivo 
Background. Cinobufagin has been widely used in the treatment of carcinoma and plays an important role in the relief of cancer pain. But the involved mechanism remains unknown. Aim. To investigate the changes in thermal and mechanical hyperalgesia in paw cancer pain in mice and the action mechanism of cinobufagin using a paw cancer pain model. Methods. 60 female mice were randomly divided into 5 groups: control group, model group, cinobufagin group, cinobufagin +NAL-M group, and morphine group; except ones in control group, mice were inoculated with H22 hepatoma cells in the right hind paw. From the 9th day after inoculation, mice were administrated drug once daily lasting for 8 days. The pain behavior was determined on the 2nd, 4th, 6th, and 8th days before and after administration. On the last day, they were sacrificed. The levels of β-END, CRF, and IL-1β were analyzed by ELISA; immunohistochemistry was performed to detect the expressions of β-END, POMC, and μ-OR in the tumor and adjacent tissue. Results. The thresholds of thermal pain and mechanical pain were significantly increased by cinobufagin. Moreover, the expressions of β-END, CRF, POMC, and μ-OR were significantly upregulated by cinobufagin. The analgesic effect of cinobufagin was blocked by the peripheral opioid receptor antagonist NAL-M. Conclusions. Cinobufagin significantly relieved cancer pain in mice and raised their pain threshold, mainly upregulating the expression levels of β-END and μ-OR in the hind paw tumor and adjacent tissue.
PMCID: PMC3800629  PMID: 24187573
24.  Molecular Identification of Ancylostoma caninum Isolated from Cats in Southern China Based on Complete ITS Sequence 
BioMed Research International  2013;2013:868050.
Ancylostoma caninum is a blood-feeding parasitic intestinal nematode which infects dogs, cats, and other mammals throughout the world. A highly sensitive and species-specific PCR-RFLP technique was utilised to detect the prevalence of A. caninum in cats in Guangzhou, southern China. Of the 102 fecal samples examined, the prevalence of A. caninum in cats was 95.1% and 83.3% using PCR-RFLP and microscopy, respectively. Among them, the prevalence of single hookworm infection with A. caninum was 54.90%, while mixed infections with both A. caninum and A. ceylanicum were 40.20%. Comparative analysis of three complete ITS sequences obtained from cat-derived A. caninum showed the same length (738 bp) as that of dog-derived A. caninum. However, the sequence variation range was 98.6%–100%, where only one cat isolate (M63) showed 100% sequence similarity in comparison with two dog-derived A. caninum isolates (AM850106, EU159416) in the same studied area. The phylogenetic tree revealed A. caninum derived from both cats and dogs in single cluster. Results suggest that cats could be the main host of A. caninum in China, which may cause cross-infection between dogs and cats in the same area.
PMCID: PMC3794661  PMID: 24175305
25.  Characterization of Four Type IV Pilin Homologues in Stigmatella aurantiaca DSM17044 by Heterologous Expression in Myxococcus xanthus 
PLoS ONE  2013;8(9):e75105.
As prokaryotic models for multicellular development, Stigmatellaaurantiaca and Myxococcus xanthus share many similarities in terms of social behaviors, such as gliding motility. Our current understanding of myxobacterial grouped-cell motilities comes mainly from the research on M. xanthus, which shows that filamentous type IV pili (TFP), composed of type IV pilin (also called PilA protein) subunits, are the key apparatus for social motility (S-motility). However, little is known about the pilin protein in S. aurantiaca. We cloned and sequenced four genes (pilASa1~4) from S. aurantiaca DSM17044 that are homologous to pilAMx (pilA gene in M. xanthus DK1622). The homology and similarities among PilASa proteins and other myxobacterial homologues were systematically analyzed. To determine their potential biological functions, the four pilASa genes were expressed in M. xanthus DK10410 (ΔpilAMx), which did not restore S-motility on soft agar or EPS production to host cells. After further analysis of the motile behaviors in a methylcellulose solution, the M. xanthus strains were categorized into three types. YL6101, carrying pilASa1, and YL6104, carrying pilASa4, produced stable but unretractable surface pili; YL6102, carrying pilASa2, produced stable surface pili and exhibited reduced TFP-dependent motility in methylcellulose; YL6103, carrying pilASa3, produced unstable surface pili. Based on these findings, we propose that pilASa2 might be responsible for the type IV pilin production involved in group motility in S. aurantiaca DSM17044. After examining the developmental processes, it was suggested that the expression of PilASa4 protein might have positive effects on the fruiting body formation of M. xanthus DK10410 cells. Moreover, the formation of fruiting body in M. xanthus cells with stable exogenous TFPSa were compensated by mixing them with S. aurantiaca DSM17044 cells. Our results shed some light on the features and functions of type IV pilin homologues in S. aurantiaca.
PMCID: PMC3776727  PMID: 24058653

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